Bis-{8 beta-(4-N,N-diacetylaminophenoxy)ethyl{9 ether

ABSTRACT

Pharmaceutical formulations and their preparation, suitable for use in the treatment of liver fluke infections of mammals, of a compound of formula (I)   WHEREIN X and X1 are the same or different and each is hydrogen or an alkyl group having one to three carbon atoms. Also provided are novel compounds within formula (I) and processes for their preparations.   wherein R and R1 are the same or different and each is hydrogen, an optionally substituted saturated aliphatic hydrocabron group having one to seven carbon atoms, an unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or together with R5 form an alkylene group having two to four carbon atoms; R2 and R3 are the same or different and each is hydrogen, a lower alkyl group having one to four carbon atoms or R5CO wherein R5 is hydrogen, an optionally substituted saturated aliphatic hydrocarbon group having one to seven carbon atoms, an unsaturated aliphatic hydrocarbon group having two to four carbon atoms, or taken together with R and/or R1 forms an alkylene group having two to four carbon atoms; and A is -CH2-, -(CH2)2-,-CH2-OCH2-or the group

United States Patent [191 Harfenist [451 Jan. 21, 1975BIS-[BETA-(4-N,N-DIACETYLAMINO- PHENOXY )ETHYL ]ETHER [75] Inventor:Morton Harienist, Chapel Hill, N.C.

[22] Filed: Feb. 28, 1972 [21] Appl. No.: 230,126

[52] U.S. Cl. 260/562 P, 260/239.3 R, 260/281, 260/326.44, 260/456 P,260/562 N,

[51] Int. Cl. C07c 103/38 [58] Field of Search 260/562, 325

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 749,907 6/1956England 260/562 OTHER PUBLICATIONS Raison et al. I, British J.Pharmacol. Vol. 10, pp. 191-99 (1955).

Chun-Chieh et al. Chem Abst., vol 54, col. 5528 (1960) Lammler et al.,Arzneimitte Horschung, Vol. 12, p. 15-21 (1962).

Primary ExaminerHarry I. Moatz Attorney, Agent, or FirmDonald Brown;Dike, Bronstein, Roberts, Cushman & Pfund [57] ABSTRACT Pharmaceuticalformulations and their preparation, suitable for use in the treatment ofliver fluke infections of mammals, of a compou I 2 nd of formula (I) NCO- R (I) wherein R and R are the same or different and each ishydrogen, an optionally substituted saturated aliphatic hydrocabrongroup having one to seven carbon atoms, an unsaturated aliphatichydrocarbon group having two to four carbon atoms, or together with Rform an alkylene group having two to four carbon atoms; R and R are thesame or different and each is hydrogen, a lower alkyl group having oneto four carbon atoms or R CO wherein R is hydrogen, an optionallysubstituted saturated aliphatic hydrocarbon group having one to sevencarbon atoms, an unsaturated aliphatic hydrocarbon group having two tofour carbon atoms, or taken together with R and/or R forms an alkylenegroup having two to four carbon atoms; and A 18 CH (CI-I ,CH OCH or thegroup 'l z s' fz a x x wherein X and X are the same or different andeach is hydrogen or an alkyl group having one to three carbon atoms. 7Also provided are novel compounds within formula (I) and processes fortheir preparations.

1 Claim, N0 Drawings This invention relates to ethers, their synthesis,formulations containing them, their use in the treatment of liver flukeinfections in mammals, and their use in the treatment of infections ofinsects in mammals.

Animals are infected with liver fluke when eating forage contaminatedwith encysted forms of cercariae, an intermediate stage in thelife-cycle of the fluke. The cercariae emerge from the cysts in theintestine of the host animal, penetrate the intestine wall, and maketheir way to the liver. At this stage they are microscopic in size, butgrow as they wander around the liver parenchyma. This causesconsiderable destruction of the liver tissue and can give rise to thesyndrome of acute facioliasis which normally leads to death of the hostwhen massive infections are present. If the animal survives, the flukeseventually reach the bile ducts where they mature into the adult worms.The presence of a massive infection in the bile ducts gives rise to thesyndrom of chronic fascioliasis which is a serious debilitating diseaseof the host animal. Hitherto liver fluke remedies have been known tokill only the adult and semiadult worms, and the immature worms havebeen resistant to attack by such remedies.

It has not been found that the compounds of formula (I) are effective incombatting infections of liver flukes in mammals, and are especiallyactive in combatting infections of immature worms of Fasciola spp.

. 3 r r locum-Quito N.CO.R1 (I) In formula (I), R and R are the same ordifferent and each is hydrogen, an optionally substituted saturatedaliphatic hydrocarbon group having one to seven carbon atoms, or anunsaturatedaliphatic hydrocarbon group having two to four carbon atoms,or taken together with R CO below form a 5 to 7 membered cyclic imide; Rand R are the same or different and each is hydrogen, a lower alkylgroup having one to four carbon atoms, or a group R CO wherein R ishydrogen, an optionally substituted saturated aliphatic hydrocarbongroup having one to seven carbon atoms, and unsaturated aliphatichydrocarbon group having two to four carbon atoms, or forms a cyclicimide with R and- /or R above; and A is -CH -(CH' or the group wherein Xand X are the same or different and. each is hydrogen or an alkyl grouphaving one to three carbon atoms.

When R or R is a saturated aliphatic hydrocarbon group it may besubstituted by a hydroxy group, an amino group, an N-alkylamino group,an N,N- dialkylamino group, or a carbonyl group for example an acylgroup, the alkyl and acyl groups referred to above each having from oneto four carbon atoms.

When R or R is a saturated aliphatic hydrocarbon radical having morethan two carbon atoms it may be a straight chain or branched-chain alkylgroup or a cyclic group such as a cycloalkyl group, but it is preferablya straight-chain (n-) alkyl group; when R or R is an unsaturatedaliphatic hydrocarbon group it is preferably an alkenyl group or analkylalkenyl group, said groups preferably having one ethylenic linkage.A is preferably CH2, CH2CHz""O-CH2.CH2,

Cl-l. CH --O--CI-l CH -CH -CHO-CH CH or I CH CH CH CH As a preferredsubclass within formula (I) are those Wherein X and X are the same ordifferent and each is hydrogen or a methyl group.

It is believedthat all the compounds of formula (I) are novel with theexceptions of those compounds wherein R R methyl and either R R" H whenA is CH or (CH or R R H or methyl when A is -CI-I CH -OCH .CH Thesecompounds have been previously disclosed in the chemical literature asintermediates for the synthesis of derivatives thereof, but nobiological activity has been previously ascribed to the compounds (J.Chem. Soc., 1931, 1765-71; Beilsteins Handbuch der Organischen Chemie,13, 464; and ChemicalAbstracts, I960, 54, 5528f).

It will be appreciated by persons skilled in the art that acid additionsalts may be formed by those compounds of formula (I) wherein one ormore of the groups R, R and R are saturated aliphatic hydrocarbon groupssubstituted by an amino, N-alkylamino or N,N- dialkylamino group. Unlessthe context indicates otherwise, wherever in the following reference ismade to compounds of formula (I) it should be understood that this termincludes the acid addition salts of the compounds hereinabove defined.

The compounds of formula (I) have been found active against experimentalinfections of Fasciola gigantica in mice, infections of Fasciolahepatica in rabbits and in ruminants including sheep and cattle, andinfections of Fasciola gigantica in calves.

The percentage kill of a liver fluke infection by a compound of formula(I) is of course dose dependent, and it has been found that the youngerthe worms, the lower is the dose required to combat the infection. Thusupon oral dosing of sheep infected with F. hepatica, a dose of 60 to 100mg. of one of the known compounds of formula (I) (R R=CH R =R =H; A=CH-CH OCH .CH per kilogram body weight provides a nearly completeeradication (90-l00 percent) of flukes of 3 days to 6 weeksold. In mostinstances an oral dose of about 100 to 120 mg. of this same compound perkilogram is required to provide a nearly complete eradication of liverflukes of all ages, including adult worms of 9 weeks and older; and anoral dose of to I20 mg. per kilogram typically gives a clearance of topercent even in cases of severe clinical infections. For treatment ofinfections of adult worms alone an oral dose of this compound ofbetween.

100 and 120 mg. per kilogram provides a nearly complete eradication,although the dosage can be increased to a level of up to 200 mg. perkilogram if desired.

A dose of a compound of formula (I) may be followed by a second dosewithin about 4 weeks, but practical considerations would probablydictate its administration after about 5 to 8 weeks. In the case of verylight liver fluke infections, the second dose may be delayed for as longas 8 weeks.

Since in the field, it must be assumed that animals are continuallysubject to reinfection, it is especially advantageous in practice toadminister these lower doses regularly during the appropriate season toabout 4 to 8 week intervals.

A compound of formula (I) may be used in the treatment of liver flukeinfections in mammals including F. hepatica in ruminants includingsheep, cattle, goat and buffalo, and in the pig and horse; and F.gigantica in ruminants including sheep and cattle. The compound ispreferably administered orally at a does between 40 and 200 mg. perkilogram.

In general it has been found that a dose of 80 to 120 mg. per kilogramis required to combat infections of both the mature and immature worms,and a dose of 60 to 100 mg. per kilogram for immature infections.

A compound of formula (I) may be administered for the treatment of liverfluke infections as the raw chemical, but preferably as an ingredient ofa pharmaceutical formulation which contains in addition one or moreinert carrier materials commonly used in pharmaceutical formulations asa vehicle for the active ingredient. The preferred formulations arethose suitable for oral administration, containing from 5 to 95 percentby weight of a compound of formula (I). If presented as the rawchemical, then a compound of formula (I) is preferably in the form of apowder.

In the context of the present invention, the qualification inert meansthat the carrier is pharmaceutically acceptable to the hose of theinfection to which the formulation is administered.

The presentation of an active ingredient (namely, a compound of formula(I)) in a pharmaceutical formulation may be as discrete units, such astablets, capsules or cachets, each containing a predetermined amount ofthe active ingredient; as a powder or granules; or as a solution or asuspension in an aqueous liquid, a nonaqueous liquid, or a water-in-oilliquid emulsion. The active ingredient may also be presented as a bolus,electuary or paste; in the feed or a feed supplement intended for thehost animal; in pellets, salt licks or block licks which are especiallysuitable for large animals such as sheep and cattle.

The formulations may be made by any of the methods of pharmacy but allmethods include the step of brining into association by admixture theactive ingredient with the carrier which constitutes one or moreaccessory ingredients. In general the formulations are prepared byuniformly and intimately brining into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product into the desired formulation. Theformulations contain one or more of the usual accessory ingredients usedto prepare anthelmintic formulations including: solid and liquiddiluents (for example, lactose, sucrose, glucose, starches, dicalciumphosphate or calcium phosphate for tablets, granules, dispersible andwettable powders, cachets and capsules; arachis oil, olive oil, or ethyloleate for soft capsules; water, or vegetable oil for aqueous andnonaqueous suspensions, emulsions, and pastes); binders (for example,starch, sugar, glucose, methyl cellulose, gum acacia, Irish moss orgelatin for granules and tablets); surface active agents (for examplesodium lauryl sulphate, cetrimide or polyoxyethylene sorbitanmonolaureate for tablets, powders and granules; sodium salt of an alkylnaphthalene sulphonic acid, sorbitan monooleate, ceto-stearyl alcoholand an emulsifier condensate of nonylphenol and ethylene oxide, forpastes and wettable powders); lubricating agents (for example liquidparaffin, talc, stearic acid, magnesium stearate or polyethylene glycolfor tablets); dispersing agents (for example, disodium salt of thecondensation product of naphthalene sulphonic acid and formaldehyde, andcalcium lignin sulphonate for wettable powders, pastes and suspensions);gelling agents (for example colloidal clays, sulphuric esters of apolysaccharide for aqueous suspensions); suspending and thickeningagents (for example gum tragacanth, xanthan gum, alginates, polyvinylpyrrolidone, sodium carboxymethyl cellulose, and hydroxy-ethylcellulosefor aqueous suspensions, aqueous based pastes and wettable powders); andhumectants (for example glycerine for water-based pastes); and othertherapeutically acceptable accessory ingredients such as preservatives,buffers and antioxidants, which are known to be useful as carriers insuch formulations.

A tablet may be prepared by compression or moulding, optionally with oneor more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Conveniently each tablet contains from 0.5g to 4.0g ofthe active ingredient.

Granules may be made by the technique of wet granulation comprisingmoistening the powdered active ingredient with a binder in an inertliquid, and drying the moist mass; or by the techniques ofprecompression or slugging. The granules may be administered to animalsin an inert liquid vehicle; or in a cachet or capsule of hard or softgelatin preferably with a liquid or powdered solid diluent; or insuspension with a water or an oil base. In a drench or suspension, it ispreferable to include further accessory ingredients such as a dispersing agent.

A dispersible or wettable powder may be made by admixing together thefinely divided active ingredient with a wetting agent, and thenadministering the powder to the host animal as a suspension ordispersion in water. If desired a dispersing, suspending or thickeningagent may be included. These formulations preferably contain from about15 to 85 percent by weight of the active ingredient.

A paste may be formulated in a liquid diluent which suspends the activeingredient. A stiffening or thickening agent may be included, togetherwith a wetting agent and an humectant if the liquid diluent is water. Ifan emulsion paste is needed (oil-out or water-out), then one or moresurface active agents should be included. From about 25 to percent byweight of these paste formulations may be comprised of the activeingredient but if the lower concentrations are used, then sufficientstiffening or thickening agent should be included to provide the desiredviscosity.

Suspensions of the active ingredient in an inert liquid carrier areessentially the same as pastes but of a lower viscosity. They may beformulated using water or other inert diluent as the liquid carrier inassociation with a dispersing or wetting agent. Other ingredients suchas thickening, gelling and suspending agents may also be included. Theseformulations may contain a wide range of concentrations of activeingredient, but of course, if too high a concentration is included theviscosity of the formulation will increase and the formulation willbecome more of a paste than a suspension. Subject therefore to theconcentration of the remaining ingredients, about 5 to 50% by weight ofthe formulations may be comprised by the active ingredient.

In feed supplements, the active ingredient is generally present in largeamounts relative to the accessory ingredients, and the supplements maybe added directly or after intermediate blending or dilution. Examplesof accessory ingredients for such formulations include solid orallyingestible carriers such as corn meal, attapulgite clay, soya flour,wheat shorts, soya grits, edible vegetable materials, and fermentationresidues. The active ingredient is usually incorporated in one or moreof the accessory ingredients and intimately and uniformly dispersed bygrinding, tumbling or stirring with conventional apparatus. Formulationscontaining about 1 to 90 percent by weight of the active ingredient areespecially suitable for adding to feeds to provide a concentrationdesired to control infections by way of the animals rations.

A compound of formula (I) may be administered either alone as the soletreatment for a liver fluke infection, or in combination with othersubstances which may complement or supplement its activity. Suchadditional substances may be administered simultaneously as a separatedose or in combination with a compound of formula (I) in a formulation,and may comprise other anthelmintics having activity against otherparasites, such as cestodes (tapeworms) or nematodes. Such additionalsubstances include phenothiazine; piperazine derivatives, for examplethe citrate, adipate or phosphate salts; organo-phosphorus compounds forexample 0,0-di-(2-chloroethyl) O-(3-chloro-4-methylcoumarin-7-yl)phosphate (Haloxon); 4-t-butyl- 2-chlorophenylN-methyl O-methyl-phosphoramidate (Ruelene (Trade Name)); 0,0-diethylO-(3-chloro-4- methyl-7-coumarinyl)phosphorothioate (Coumaphos);0,0diethyl O-naphthaloximide phosphate (Naphthalophos); 0,0-dimethyl2,2,2-trichloro-l-hydroxyethylphosphonate (Trichlorfon); benzimidazoleanthelmintics including 2-(4-thiazolyl)benzimidazole(Thiabendazole);methyl S-n-butyl benzimidazole -2- carbamate(Parbendazole); and isopropyl 2-(4- thiazolyl)benzimidazole-S-carbamate(Cambendazole); quaternary ammonium anthelmintics including N-benzyl-N,N-dimethyl-N-(2-phenoxyethyl)ammonium salts such as the3-hydroxy-2-naphthoate and embonate salts (Bephenium salts); N,N-dialkyl-4- alkoxy-a-naphthamidine anthelmintics including N,N-dibutyl-4-hexyloxy-a-naphthamidine (Bunamidine); dl-andl-2,3,5,6-tetrahydro- 6-phenylimidazo (2,1-b) thiazole salts(Tetramisole); trans-l-methyl-2-[2-(2-thienyl)vinyl]-l,4,5,6-tetrahydropyrimidine tartrate (Pyranteltartrate); cis-l,4,5,6-tetrahydro-l-methyl-2- thienyl)vinyl]pyrimidinetartrate (Morantel tartrate); polyhalogenated benzanilide anthelminticsincluding 3,3',5,5,6-pentachloro-2,2-dihydroxybenzanilide(Oxyclozanide); 2-acetoxy-4'-chloro-3, 5- diiodobenzanilide(Clioxanide); 3,4',5- tribromosalicylanilide(Tribromsalan);3,5-diiodo-3'- chloro-4-(p-chlorophenoxy)salicylanilide(Rafoxanide); 5-bromo-2-hydroxy-4'-bromobenzanilide; 2,2-dihydroxy-3,3'-dinitro-5,5-dichloro-biphenyl (Menichlopholan);2,2-dihydroxy-3,3',5,5, 6,6'-hexachlorodiphenylmethane(Hexachlorophene); 1,4-bis (trichloro-methyl) benzene (Hetol);3-iodo-4-hydroxy- S-nitrobenzonitrile (Nitroxynil); and 5-chloro-N-(2'-chloro-4'-nitrophenyl) salicylamide (Niclosamide).

A particularly preferred combination comprises a compound of formula (I)and oxyclozanide, preferably in the ratio of 40 to mg./kg. and 3 to 15mg/kg. respectively. Oxyclozanide is highly effective against adultliver flukes, and in combination with a compound of formula (I),complements its activity.

The compounds of formula (I) have been found active systemically againstinsect parasites of mammals as exemplified by activity against Stomoxyscalcitrans, the stable fly,-following oral administration to host mice.The compounds have further been found active against infection inmammals of the larvae of flies of the genus Oestrus and especiallyagainst infections of the larvae of Oestrus ovis, the sheep nasal fly. V

Animals including the sheep, goat and camel become infected by themature fly depositing the young larvae around the nostrils of the host,whence the larvae crawl upwards to live as parasites in the nasal cavityand adjoining sinuses. The larvae irritate the nasal mucosa causing thesecretion of a viscid mucous exudate; erosion of the bones ofthe skullmay occur and even injury to the brain, when locomotion of the host mayybe affected. Infected animals have a nasal discharge together with adepressed appetite which commonly results in emaciation and, in cases ofsevere infection, in death of the animal.

A compound of formula (I) may therefore be used for the treatment ofOestrus infections in mammals by producing a systemically effectiveinsecticidal concentration of the compound in the body of the mammalupon administration of the compound to the mammal. The compound ispreferably administered by the oral route; when administered in thismanner systemic activity against insect parasites has been demonstratedat a dose level of up to 200 mg. per kilogram bodyweight of host or at adose level of as little as 40 mg. per kilogram or substantially lower. Acompound of formula (I) may be administered for the treatment of insectparasites as the raw chemical, but preferably as an ingredient of apharmaceutical formulation as hereinbefore described.

Excluded from the scope of the present invention are non-sterilemixtures which are mere solutions and suspensions of the known compoundsof formula (I) as hereinbefore defined in solvents and liquids known inthe literature for use in the synthesis and isolation of the compoundsby the methods described therein. Included within the scope of thepresent invention are such known solutions and suspensions which arepharmaceutically acceptable to the host of the infection to be treatedand which contain in addition at least one other pharmaceuticallyacceptable substance.

ZAZ(II) wherein Z is a reactive nucleophilic atom or group and A is asdefined above, with an alkali metal salt of a phydroxyacylanilide of theformula (III) AlkO 1- -CO.l3 (111) wherein Alk is conveniently potassiumor sodium, B is R or R, and E is R or R, as defined above in formula(I). In formula (II), Z is preferably a halogen atom, for examplechlorine, bromine or iodine, or is ptoluene-sulphonyloxy, but otheralkanesulphonyloxy, arylsulphonyloxy or aralkylsulphonyloxy groups mayalso be used instead. The reaction is carried out in a liquid mediumwhich is preferably a polar liquid and which conveniently may be anoptionally aqueous alkanol, for example methanol, ethanol, orisopropanol, or may be dimethylsulphoxide, sulpholane,dimethylformamide, dimethylacetamide, N-methyl-Z-pyrollidone, ormixtures of the foregoing. If Z is chlorine, then it is preferable toinclude a small quantity of potassium iodine in the reaction mixture.The reactants are preferably present in about a 2 to 1 molar ratio ofthe compounds of formula (III) and (II) respectively, but a slightexcess of a compound of formula (III) is conveniently used. Thereactants may be heated together under an inert atmosphere, for examplenitrogen, at the reflux temperature of the reaction mixture. It will beappreciated that the compounds of formula (I) most conveniently preparedby this method are those in which R R and R R.

It will of course be understood that in the course of the above reactionthe compounds of formulae (IV) and (V) will be formed as transientintermediates n.co.n

N.CO.B

wherein Z, A, E and B are as defined above; and of course a compound offormula (I) may be prepared ab initio by reaction of a compound offormula (IV) or (V), with about an equimolar quantity of the compound offormula (II), under the conditions previously described above. It willbe further understood that the compounds of formula (I) wherein Rdiffers from R and R differs from R are preferably prepared in thismanner.

The compounds of formula (III) identified above may be optionally formedin situ from the corresponding phenol using such basic reagents assodium hydride, potassium hydroxide, sodium hydroxide, an alkali metalalkoxide, for example potassium tertiary butoxide, sodium ethoxide,sodium methoxide, or a mixture of an alkali metal carbonate and analiphatic ketone, for example potassium carbonate and acetone.

The compounds of formula (I) may also be prepared by the acylation of anamine of formula (VI) wherein R and R are as defined above, and whereinboth of R are hydrogen, or one is hydrogen and the other is a group M.COwhere M is one of R and R as defined above; and wherein A is as definedabove in formula (I). The acylation may be carried out by any knownmeans and conveniently in a polar or non-polar liquid medium, the natureof which is dependent upon the acylating agent used. Thus if the acid isused, it is preferred to heat the reactants in excess of the acid. If anacid anhydride is used, then water, an aromatic hydrocarbon, such asbenzene, a halogenated aliphatic hydrocarbon such as chloroform, anether such as dioxane, or an excess of the acid anhydride may be used asthe liquid medium. An aromatic hydrocarbon or an ether may also be usedas the liquid medium if an acid chloride is chosen as the reactant. Anether, an aromatic hydrocarbon or a halogenated aliphatic hydrocarbonmay also be used as the liquid medium if a ketone is used as theacylating agent. The medium may be an excess of the acylating agentabove that demanded by the equation of the reaction, for example ifusing an alkyl ester. The formamido derivatives, that is to say thosecompounds of formula (I) wherein either or both of R and R are hydrogen,are preferably prepared by the use of formic acid, which may be presentin excess to act as a solvent.

The compounds within formula (I) wherein either or both of the groups Rand R are saturated aliphatic hydrocarbon groups substituted by anamino, N- alkylamino or N,N-dialkylamino group may. also be prepared bythe reaction of ammonia or a primary or secondary alkyl amine, asappropriate, with the corresponding halo-substituted compound and thislatter may itself be prepared from the amine of formula (VI) byhaloacylation using, for example, a halo-substituted monocarboxylic acidsuch as monochloracetic acid.

Those compounds as hereinabove defined within formula (I) that form acidaddition salts may be isolated as such or as the base thereof and may beoptionally converted, as appropriate, to the base, an acid addition saltthereof or the salt of another acid by methods known in the art.

According to the present invention there are therefore provided thenovel compounds of formula (I); and pharmaceutical formulationscomprising the compounds of formula (I) in association with an inertcarrier therefor; and methods of making such novel compounds and suchpharmaceutical formulations. The present invention also provides amethod for the treatment of infections of liver flukes in mammalscomprising the administration to the host of the infection an effectiveamount of a compound of formula (I). The present invention also providesa method for producing a systemically effective insecticidalconcentration of a compound of formula (I) in the body of a mammalcomprising the administration to the mammal of said compound.

In the Examples Nos. 1 to 23, 26 and 27, the compound of formula (I)therein referred to is bis-[B-(4- acetamidophenoxy)ethyl] ether. Thenumbered Examples of the invention are included to indicate the precisemanner in which the invention may be put into practice, and should notbe construed as limiting in anyway the scope of the invention disclosedin this specification.

The following are examples of the synthesis of bis-[B-(4-acetamidophenoxy)ethyl] ether.

Synthesis of bis-[B-(4-acetamidophenoxy)ethyl] ether To a solution ofp-hydroxyacetanilide (169 g., 1.12 M) in dimethyl sulphoxide (590 ml.)was added potassium tertiary butylalcoholate (112.5 g., 1.0 M). Thereaction mixture spontaneously heated from about 50C to 90C and turnedgreen. After stirring under nitrogen for about 5 minutes,bis-(B-chloroethyl) ether (82.5 g., 0.585 M) was added dropwise overabout minutes with stirring. The reaction mixture was stirred overnight,and the majority of the dimethyl sulphoxide evaporated off. Theremaining liquid was diluted with about 3 times its volume of water andthe precipitate filtered to provide crystals, m.p. 105 110C. After tworecrystallisations from a water/ethanol mixture, and washing withethanol, the product had an initial m.p. l41.3 to 141 .7C. On raisingthe temperature, the compound solidified and then remelted at l6l162C.

Further synthesis of bis-[/3-(4-acetamidophenoxy)ethyl] ether Compoundof formula Bentonite ((iclling Agent Bevaloid Dispersant (Trade Mark)(Dispensing agent) Sodium Benzoute (Buffering agent) Water Furthersynthesis of bis-[B-(4-acetamidophenoxy)ethyl] ether Compound of formula(I) Sulphitc Residue (Dispersing agent) (urmoss ((ielling agent) (TradeMark) Water mixture was diluted with aqueous hydrochloric acid ml. ofN-acid), then with water (300 ml.), and the mixture filtered to removethe platinum and a little solid. The filtrate was treated with aceticanhydride (50 ml.), and then with aqueous sodium hydroxide (50%), untilthe mixture was pH 9 to 10. Further acetic anhydride was added (50 ml.),the solution heated, charcoal added to remove colour, filtered, andwater added to precipitate bis-[B-(4-acetamidophenoxy)ethyl] ether whichwas found to have an initial melting point of l42.7 to l43.lC. Onraising the temperature, the compound resoliditied and then remelted at154C.

Further synthesis of bis-[B4 4-acetamidophenoxy)ethyl] ether.

Sodium (5.1 g., 0.22 M) was dissolved in dried ethanol (200 ml.), andp-hydroxyacetanilide (33.2 g., 0.22 M) was added to the warm solution.After the anilide had dissolved, bis-(B-chloroethyl) ether (1 1.7 ml.,0.10 M) and potassium iodide (10 g.) were added and the mixture wasrefluxed with stirring for 16 hours. After removing a greater part ofthe ethanol by distillation in vacuo, the residue was poured into water(500 ml.), the precipitate filtered off and washed with aqueous sodiumhydroxide (2N) and water. After drying, the product was recrystallizedfrom industrial methylated spirits, and had a melting point of 142C. Onraising the temperature, the compound resolidified and then remelted atl6l2C.

Further synthesis of bis-[1H4-acetamidophenoxy)ethyl] ether.

Sodium (0.80 g., 0.035 M) was dissolved in dried ethanol (40 ml.) andp-hydroxyacetanilide (5.45 g., 0.036 M) was added to the warm solution.After the phydroxyacetanilide had dissolved, bis-[0(4-toluenesulphonyloxy)ethyl] ether (6.60 g., 0.016 M) was added and themixture refluxed with stirring for 24 hours. After concentration of thereaction mixture in vacuo and pouring it into water, a precipitate wasfiltered off, washed with aqueous sodium hydroxide (2N) and water. Afterdrying the product was recrystallised from methylated spirit, final m.p.l6l2C.

EXAMPLE 1 AQUEOUS SUSPENSIONS (I) 5.0% 20.00% 40.00% 50.00% w/w Thebentonite was dispersed in some of the water, the Bevaloid Dispersantand sodium benzoate added, and finally the finely ground activeingredient and balance of the water. The whole was mixed until uniform.

Bentonite is a colloidal clay consisting principally of montmorillonite,Al O HSiO l-l O, and Bevaloid Dispersant is disodium salt of thecondensation product of naphthalene sulphonic acid and formaldehyde.

EXAMPLE 2 AQUEOUS SUSPENSIONS The Carmoss and sulphite residue weredissolved in ground active ingredient. The whole was mixed until thewater, the finely ground active ingredient added, uniform. and the wholemixed until uniform. Gum Tragacanth is the dried mucilaginous exudationSulphite residue is crude calcium lignin sulphonate; from the Astragalusspecies. Carmoss is a carragenate or a sulphuric acid ester of a 5polysaccharide. EXAMPLE 5 AQUEOUS SUSPENSIONS Compound o1 formula (I)20.00% w/w 50.00% w/w 5.0% w/w Keltrol (Trade Mark) (suspending agent)0.20% do. 010% do. 03% do. Bcvaloid Dispersant (Trade Mark) 1.00% do.l.00% do. 1.0% do. Water 78.80% do. 48.90% do. 93.7% do 100.00% w/w100.00% w/w 100.00% w/w EXAMPLE 3 AQUEOUS SUSPENSION The Keltrol wasdissolved in the water, the Bevaloid c d H I (I) 5 07 I Dispersantadded, and finally the finely ground active ompoun 0 ormu a 0 W W Neosyl(mum) 5.0% m ingredient. The whole was mixed until uniform wg g age t)20 Keltrol 1s a xanthan gum, a high molecular weight lin- (Trade ar 1.5do. Bevaloid Dispersant ear polysacchande' (Dispersing agent) 1.0 do. M

100.0% wlw EXAMPLE 6 AQUEOUS SUSPENSlONS Compound of formula (I) 20.00%w/w 50.00% w/w 5.00% w/w Manucol (Trade Mark) (suspending agent) 0.25%do. 0.15% do. 0.40% do. Bcvaloid Dispersant (Trade Mark) (Dispcrsingagent) 1.00% do. 1.00% do. 1.00% do. Water 78.75% do. 48.85% do. 93.60%do.

100.00% w/w |00.00'/, w/w 100.00% w/w The Carmoss and BevaloidDispersant were mixed The Manucol was dissolved in the water, theBevawith the water, and then the finely ground active ingreloidDispersant added, and finally the finely ground acdient and the Neosyladded. The whole was mixed until tive ingredient, the whole being mixeduntil uniform. uniform. Manucol is a sodium alginate.

Neosyl is a diluent of finely prepared silica which 40 functions as astiffening agent. EXAMPLE 7 AQUEOUS SUSPENSIONS Compound of formula (I)20.00% w/w 50.00% w/w 5.00% w/w Bevaloid Disperant (Trade Mark)(Dispensing agent) 1.00% do. 1.00% do. 1.00% do. Sodium hcnzoate(Buffering agent) 1.00% do. 1.00% do. 1.00% do. Polyvinyl pyrrolidone(PVP 90) (suspending agent) 8.00% do. 6.00% do. 15.00% do. Water 70.00%do. 42.00% do. 78.00% do.

100.00% w/w 100.00% w/w |00.00'/ w/w I EXAMPLE f1 AQUEOUS SUSPENSIONS 55The polyvinyl pyrrolidone was dissolved in the water The gum tragacanthwas dissolved in the water, the with stirring, and when dissolved theBevaloid Disper- Bevaloid Dispersant then added and finally the finelysant and sodium benzoate added. Finally the finely ground activeingredient was added and mixed until uni- The Gum Arabic was dissolvedin the water, the form. Bevaloid Dispersant and the finely ground activeingre- Polyvinyl'pyrrolidone is a polymerised form of v'inyldient added,and the whole mixed until uniform. pryollidone. Gum Arabic is the driedexudation from the stem and 5 branches of Acacia senegal.

EXAMPLE 8 AQUEOUS SUSPENSIONS EXAMPLE 10 AQUEOUS SUSPENSIONS Compound offormula (I) 5.0% w/w 20.00% w/w 50.0% \v/w Bevaloid Dispersant (TradeMark) (Dispersing agent) 1.0% do. 1.00% do. 10% do. Sodium Bcnzoate(Buffering agent) l.0'/r do. 1.00% do. 10% do. Courlose F.700 (TradeMark) (Suspcnding agent) 1.0% do. 0.60do. 0.5% do, Zircomplex P.A.(Trade Mark) (suspending agent) 2.5% do. |.60% do. l.25% do. Water 89.5%do. 75.80% do.. 46.25% d 100.0% W/W 100.00% w/w 100.0% w W Compound ofl'orn1u|a(l) 20.0% \v/w 50.0% w/w 5.0% w/w Bevaloid Dispersant (TradeMark) (Wetting agent) l.0'/ do. 10% do. L05; do. Courlose F 700 (TradeMark) (suspending agent) 1.0% do. 0.5% do. 1.0% do. Water 78.05600.48.5% do. 92.0% do.

100.0% w/w 100.0% w/w 100.0% w/w The Courlose was dissolved in thewater, the Zircom- 30 the Courlose F 700 was dissolved in the water, theplex P.A. then added, followed by the Bevaloid Disper- BevaloidDispersant and the finely ground active ingresant and sodium benzoateand'finally the finely ground dient added, and the whole mixed untiluniform. active ingredient. The whole was mixed until uniform. CourloseF 700 is sodium 'carboxymethylcellulose.

Courlose F 700 is the sodium salt of carboxymethyl- 5 EXAMPLE (1 AQUEOUSSUSPENSIONS Compound of formula (I) 20.0% W/W 50-07! W/W 5.071 w/wBevaloid Dispersant (Trade Mark) (Wetting agent) l.0% do. (.0% do. l.0%do.

Natrosol 250 (Trade Mark) (suspending agent) 0.05% do. 0.03% do. 0.l%do.

Water 714.95% do. 40.97% at). 9% do 100.00% w/w 100.00% w/w 100.00% w/wcellulose; Zircomplex PA. is an organic complex of zirthe Natrosol wasdissolved in the water, the Bevaloid comum. Dispersant and the finelyground active ingredient added, and the whole mixed until uniform. 50Natrosol 500 is hydroxyethylcellulose.

EX PLE noueous S USPENSIONS EXAMPLE 12 OIL-BASED PASTES Compound offormula (l) 20.00% w/w 50.0% w/w 5.0% w/w Bevaloid Dispersant (TradeMark) (Dispensing agent) l.0'// do. I.()% do. 10% do. Gum Arabic(Thickening agent) 0.5% do. 0.3% do. 2.0% do. Water 785% do. 48.7% do.92.0% do.

100.0% w/w 100.0% w/w 100.0% w/w China clay (Solid Diluent) 20.0% w/wMineral Oil (Liquid Diluent) 50.0% w/w 40.0% w/w (10.0% w/w 60.0% do,Compound of formula (l) 50.07! do. 60.0% do. 40.0% do. 20.0% do.

100.0% w/w 100.0% w/w 100.0% w/w 100.0% w/w The components were mixed insuitable equipment, Bentone 38 is a cationic bentonjte substituted witha to provide pastes of uniform consistency. quaternary ammonium base.

Mineral oil is a high boiling fraction of a refined pertroleum 01]containing not less than 96% unsulphonata- EXAMPLE l5 WATER-BASED PASTESCompound of formula (I) 23.0% 55.00? (0.00) 45.00, Kcltrol (Trade Mark)(suspending agent) 0.5% 0.50% 0.45% 0.55; tin. Ncosyl (Diluent) 18.3%5.00% Glycerine (Humeetant) 23.0% 20.00% 04.00% 22.00% do. Water 35.2%24.50% 10.55% 32.45% do 100.0% 100.00% 100.00% 100.00% w/w ble material.The Keltrol was dissolved in the water, the remaining ingredientsincorporated, and the whole mixed until EXAMPLE l3 OIL-BASED PASTESuniform.

Mineral 011 (Liquid Diluent) 10.0% 40.0% 32.0% 49.5% w/w Vaseline(Thickening agent) 70.0% 10.0% 8.0% 5.5% 00. Compound of formula TheVaseline was dissolved in the mineral oil and the Keltrol is a xanthangum, a high molecular weight linfinely ground active ingredient addedand mixed in ear polysaccharide. suitable equipment until uniform.

Vaseline is petroleum elly. EXAMPLE l6 WATER-BASED PASTES Compound offormula (I) 20.0% 50.00% 60.00% 40.00% w/w Bevuloid Dispersant (TradeMark) (Dispcrsing agent) 0.5% 0.50% 0.40% 0.60% do. Gum Tragucanth(Suspending agent) 3.5% 2.00% 1.60% 2.40% do. Glycerine (Humeetant)16.0% 8.50% 8.00% l 1.00% do. Water 00.0% 39.00% 30.00% 46.00% doEXAMPLE 14 OIL-BASED PASTES The gum tragacanth was dlssolved 1n themixture of China clay (Solid Diluent) 30.00% w/w Mineral Oil (LiquidDilucnt 46.75% 36.25% 46.75% 51.00% do. Bentone 38 (Trade Mark)(Thickening agent) 2.50% 2.75% 2.50% 3.00% do. Industrial methylatedspirits 0.75% 1.00% 0.75% 1.00% do. Compound of formula 100.00% l00.00%I00.(l0% 100.00% W/W The Bentone 38 was added to the mineral oil, andwater and glycerine,and the finely divided active ingrestirredvigorously for 15 minutes, after which time the dient incorporated toprovide a uniform paste. methylated spirits were added and the wholestirred for a further minutes. The finely ground active ingredi- EXAMPLE17 PASTES Compound of formula (I) 50.0% 60.0% 50.0% 60.0% 20.0% w/wPolyethylene Glycol 400 40.0% 32.0% 50.0% 40.0% 45.0% w/w PolyethyleneGlycol 4000 l0.0% 8.0% 5.0% w/w China clay (Solid diluent) 30.0% w/w100.0% I 00.0% [00.0% I 00.0% l00.0% w/w ent was then added and thewhole mixed until uniform. Both glycols, or the single glycol, asappropriate, Where China clay was an ingredient, it was included at wereheated together, and when uniform, the finely the same time as theaddition of the compound of forground active ingredient, (together withthe China mula (I). V clay, if appropriate) was added, and the mixturestirred 3,862,226 in g 17 18 to provide a paste of uniform consistency.The raw materials were mixed together to provide a powder of uniformconsistency. Perminal BX is the so- EXAMPLE PASTES dium salt ofalkylated naphthalene sulphonic acid.

Compound of formula 50.0% w/w 60.0% w/w 40.0% w/w 20.0% \v/w Carmoss(Trade Mark) (Thickening agent) 2.0% do. 1.0% do. 2.5% do. 1.7% do.(ilyccrinc (Humectnnt) l0.0'// do. 8.0% do. 12.0% do. 8.3% do. water33.0% do. 30.4% do. 45.5% do. H.771 do. China clay (Solid Dilucnt) 38.3%do.

100.0% w/w 100.0% w/w 100.0%w/w 100.0% w/w the Carmoss was dissolved inthe water, the glycerine EXAMPLE 22 FEED PREMIXES added, followed by theactive ingredient (and China Clay, if appropriate). The whole was mixeduntil unif Compound of formula (I) 1% w/w 80% w/w Cereal Base 99% do.do. Carmoss 1s a carragenate or a sulphurlc acid ester of a o]saccharide.

p y The two materials were mixed to provide a premix of EXAMPLE l9PASTES 20 uniform consistency.

Compound of formula 60.0% w/w 70.0% w/w 45.0% W/W 20.0% w/w Manucol(Trade Mark) (Thickening agent) 0.3% do. 0.25% do. 0.4% do. l.5'/r do.Glyccrinc (Humcctant) 8.0% do. 6.00% do. ll.0// do. 5.0% dov Water 31.7%do. 23.75% do. 43.6% do. 38.5% do. China clay (Solid Dilucnt) 35.0% do.

100.0% w/w 100.0% w/yy 100.0% w/w 100.0% w/w The Manucol was dissolvedin the water and glycer- EXAMPLE 23 PELLETS inc and the activeingredient (and China Clay, if appropriate) added and mixed untiluniform.

Compound of formula (I) l% 80% Manucol is sodium algmate. 35 Cereal Base99% 20% EXAMPLE 20 OIL-IN-WATER EMULSION PASTES The two ingredients weremixed, and the mixture Compound of formula (I) 5.0% w/w 50.0% w/w SipolWax A0 (Trade Mark) (Emulsifying agent) 6.25% do. 5.0% do. Mineral Oil(Liquid Dilucnt) 25.0% do. 200% do. Water 31.25% do. 25.0% do. ChinaClay (Solid Diluent) l7.50% do.

100.0% w/w V I 100% w/w The Sipol wax AC was dissolved in the mineralOil at then fed to any conventional feedstuff pelleting plant. 60C, andthis solution then added with vi orous stirring to the water, also at60C. Stirring was continued EXAMPLE 24 until the emulsion was cooled to25 C, at which Tablets were prepared from the followingingreditemperature the finely ground active ingredient (and m the ChinaClay where appropriate) was added, and the whole mixed until uniform.

per table! slpol wax AG ls Cetomacrogol Emulslfymg Wax l.Bis-[B-(4-acetamidophenoxy)ethyl] ether 2000 mg. 2. Starch B.P. 300 mg.-3. Providone B.P.C. 50 mg, EXAMPLE 21 WETTABLE POWDERS 4. Magnesiumstearate HP. 25 mg.

Compound of formula (I) 85.0% w/w 20.0% w/w Ncosyl (Trade Mark)(Dilucnt) 1.0% do. 24.0% do. Bevaloid Dispersant (Trade Mark)(Dispersing agent) 2.0% do. 2.0% do. Pcrminal BX (Trade Mark) (Wettingagent) 0.2% do. 0.2 do. Natrosol 250 (Trade Mark) (suspending agent)1.7% do. 2.8% do. Sodium sulphate (suspending agent) l().l% do. 51.0%do.

LIIbUN EXAMPLE 25 Tablets were prepared from the following ingredients:

per tablet 2000 mg. 1000 mg. 50 mg. 250 mg. 30 mg.

Bis-[B-(4-acetamidophenoxy)ethyl] ether Microcrystalline celluloseMethylhydroxyethylcellulose Starch B.P.

Magnesium stearate Item 1, together with half the quantity of items 2and 4, were granulated with a solution of item 3 in 50 percent aqueousethanol, and then dried. The remainder of items 2 and 4 were added, andthen item 5, and the whole mixed together. The resulting granules weredried and then compressed to form tablets.

EXAMPLE 26 TREATMENT OF F. HEPATICA No. of animals Age of F. heparica attime of treatment (weeks) Group No. Dose (mg/kg) 1 100 6 ll l 8Untreated Controls mbh Each dose was calculated individually on thebasis of bodyweight on the day before treatment. The dose was suspendedin water, to which a little Hederol (a wetting agent, sold by Proctor &Gamble) was added, and given by drenching bottle.

The sheep were slaughtered ten to eleven weeks after infection and thelivers were examined. The following result ere QWEPPQ;

Mean No. Dose Age of F. hepatica F. heptalica Percent- (mg/kg) at timeof treatment found age (weeks) post mortem clearance 100 6 1.0 99 100 82.75 97 Untreated controls 83 In the same experiment, hexachlorophene ata dose of 10 mgjkg. gave clearances of 67 and 71 percent of 6- and8-week old liver fiukes.

EXAMPLE 27 A further experiment was conducted in the manner described inExample 26, except that the sheep were dosed at 3 and 5 weeks with thecompound of formula (I). The following results were obtained:

Dose Age of F. hepalica Mean No. I". hepalica (mg/kg.) at time oftreatment found post mortem (weeks) at 6 weeks 9 (stunted) Controls 3377 l00 I25 EXAMPLE 28 Synthesis ofbis-[B-(4-formamidophenoxy)ethyllether A mixture ofB,B'-bis-(4-aminophenoxy)ethyl ether (28.8 g.) and formic acid (23 ml.of 98-100percent) was mixed and heated overnight on a steam bath. Themixture was then poured with stirring into cold water (500 ml.). Theresulting crystals were filtered from the supernatant liquid, and washedwith water, to leave a crystalline solid mp. 15 l- C. This solid wasrecrystallized from hot ethanol (about 1.4 litre, 95percent) by addinghot water (about 1 litre), charcoaling while hot to remove most of thecolour, filtering, and adding more water (about 1.5 litre) to thefiltrate. The resulting solid m.p. l56.5-l57C, was again recrystallizedfrom an ethanol-water mixture, m.p.' 156C.

Analysis: Calculated for C I-1 N 0 C,62.78; H, 5.85; N, 8.14.

Found: C, 62.80; H, 5.80; N, 8.10.

EXAMPLE 29 Synthesis of B-(4-acetamidophenoxy)ethyl/3-(4-propionamidophenoxy)ethyl ether p-Propionamidophenol (30 g.)dissolved in dry dimethylsulfoxide (200 ml.) was treated in a nitrogenatmosphere with potassium tertiary butoxide (18.5 g.). After having beenstirred for about 10 minutes, the reaction mixture was treated withB-chloroethyl [3'-(4- acetamidophenoxy)ethyl ether (39 g.), and heatedand stirred on a steam bath in a nitrogen atmosphere for 26 hours. Thesolution precipitated a voluminous purplishwhite solid on treatment withwater (700 ml.). The solid was filtered from the aqueous solution, andwashed with water. It had m.p. 137.2138.4 C. It was recrystallized froma hot ethanol-water mixture, charcoal added and the mixture filteredwith a little filteraid, to gave a product of the same m.p. This wasrecrystallized again to give a first crop of off-white crystals meltingon slow heating at 136.5 C. A tan coloured second crop m.p. 135 C cameout later.

Analysis: Calculated for C ,H N O Molecular Weight 390.44: C, 65.62; H,6.71; N, 7.18.

Found; C, 65.51; H, 6.83; N, 7.18.

EXAMPLE 30 Synthesis of B-(4-acetamidophenoxy)ethylB-(4-formamidophenoxy)ethyl ether B-ChloroethylB'-(4-acetamidophenoxy)ethyl ether (38.5 g.; 95 percent by assay; 0.142Mole) was added to a stirred solution of p-formamidophenol (24.3 g.,0.18 Mole) and potassium tertiary butoxide (18 g.) (added in that orderunder nitrogen) in dry dimethyl sulfoxide (100 ml.). After addition ofmore dimethyl sulphoxide (100 ml.), the reaction mixture was stirred andheated on steam under nitrogen for 48 hours. It was then poured intowater (about 2 litres), scratched to induce partial crystallization, andstored at 4 C. overnight. Decantation of some crystals and the aqueoussolution from a matrix of crystals in oil, trituration of the latterwith ether and filtration of the resulting solution-suspension, left alargely solid mass. Meanwhile, filtration of the alkaline aqueousdecantate (above) gave crystals m.p. 100101 C, depressed in m.p. onadmixture with starting halo-ether of m.p. 9798 C.

The residue of the ether trituration melted poorly at about 76.581 Cafter one recrystallization from an ethanOLbenZene-heXane mixture. Itwas then recrystallized from acetone water, charcoaling to removecolour. It crystallized slowly after seeding and scratching repeatedly,to give a product m.p. l02.5104C. This was again recrystallized fromacetone water for analysis, m.p. 105.2108 C. Thin layer chromatographysuggested the presence of or less of bis-[B-(4- acetamidophenoxy)ethyl]ether.

Analysis: Calculated for C,,H,,N,O,, Molecular Weight 358.39: C, 63.17;H, 6.23; N, 7.69. Found: C, 63.87; H, 6.28; N, 7.70.

EXAMPLE 31 Synthesis of bis-[fi-(4-butyramidophenoxy)ethy1]etherCalculated Found Analysis:

EXAMPLE 32 Synthesis of bis-[/3-(4-lactamidophenoxy)ethyl]ether Amixture of bis-[B-(4-aminophenoxy)ethyl] ether (17.1 g., 0.059 M) andethyl lactate (40 ml., 0.36 M) were heated for about 50 hours until nomore ethanol distilled off. The mixture was then evaporated to drynessin vacuo and extracted with hot water 1,500 ml. Concentration andcooling of the aqueous extracts caused precipitation of crystals, m.p.127129C.

Calculated Found Analysis:

bJb-l EXAMPLE 33 Synthesis of bis-(4-acetamidophenoxy)methane A solutionof p-hydroxyacetanilide (14.1 g.) and potassium tertiary butoxide (1 1.2g.) in dimethyl sulphoxide (25 ml.) was added to methylene chloride(20.0 g.) dissolved in dimethyl sulphoxide (25 ml.) in a pressurebottle. The mixture was heated on a steam bath for 3 days, cooled, andpoured into water (500 ml.). The precipitate which formed was filteredand washed with 0.5N sodium hydroxide 1500 ml.) and then with water (500ml.). Recrystallisation from aqueous ethanol Synthesis ofbis-[B-(4-acetamidophenoxy)isopropyl]ether acetamidophenoxy)isopropyl1ether, m.p. 166166.5C.

Analysis: Calculated C,65.98 H,7.05 N,7.00 Found -.C,65.76 C,7.08 N,6.94

EXAMPLE 35 Synthesis of bis-[B-(4-pivalamidophenoxy)ethyllether Asuspension of bis-[B-(4-aminophenoxy)ethyl]ether (28.9 g., 0.1M) inpyridine (19.5 g., 0.245M) and dry tertiary butanol ml.) was added towarm (about 60C.) pivalyl chloride with stirring. An exothermic reactionoccurred and the mixture was allowed to stand for 35 minutes after theaddition was complete before being added to water (700 ml.). Thecrystals which slowly formed were recrystallised with charcoaling fromaqueous ethanol (about 70 percent) to give bis-[B-(4-pivalamidophenoxy)ethyl]ether, m.p. 153.7 154.4C.

Calculated Found Analysis: :C,68 9 :C,68 4

EXAMPLE 36 p-Acetamidophenol (332 g.) dissolved in dry dimethylsulfoxide(900 ml.) was treated under a nitrogen atmosphere with potassiumtertiary butoxide (234 g.) with sufficient cooling to maintain thetemperature below about 65C. The reaction mixture was stirred and cooledto room temperature. B,B-bischloroethyl ether (577 g.) was added and thereaction mixture heated with stirring on a steam bath for 24 hours undera nitrogen atmosphere. The reaction mixture, reduced to about 750 ml. bydistillation in vacuo, was poured into water (2.5 l.) and extracted withether. The ether extracts and an ether-insoluble organic phase werecombined and distilled. B-Chloroethyl /3-(4- acetamidophenoxy)ethylether was collected at l93-206C. and 550-600 microns and thenrecrystallized from ethanol-water, m.p. 100.6-10l.6C.

Calculated for C,,H, NO,-,Cl: C,55.92; Found: C,56.10;

This compound was used in the syntheses described in the foregoingExamples 29 and 30.

EXAMPLE 37 Synthesis of bis-[[3-( 4-acetoacetamidophenoxy)ethyl]etherbis-[fl-(4-Aminophenoxy)ethyl]ether (57.6 g.) dissolved in acetone (300ml.) was treated with 450 ml. of 50 percent diketene in acetone. Thereaction mixture was warmed and filtered through a filter-aid using 1.5l. of warm acetone washes. The filtrate was cooled to 30C. and wateradded to incipient turbidity. It was then stored at 4C. duringcrystallization. The bis-[B- (4-acetoacetamidophenoxy)ethyl]ether wasrecrystallized from acetone, m.p. 129.2 129.7C.

Calculated for C,,H,,N,O,: C.63.l5; Found: C,63.29;

EXAMPLE 38 Synthesis of Bis-[H4N-Methyl-p-Acetamidophenoxy)Ethyl] EtherTo p-Methylaminophenol sulphate (344 g.), suspended in percent ethanol(1,500 ml.), was added,

over a 20 minutes period with warming and stirring under a nitrogenatmosphere, acetic anhydride (307 g.) and 40 percent sodium hydroxide(285 ml.). The reaction mixture was allowed to stand overnight and theresulting product removed by filtration, washed with water, andrecrystallized from ethanol to give N-methyl-pacetamidophenol (381 g.),m.p. 241.5243C.

Potassium tertiary butoxide (112 g.) was added to a solution ofN-methyl-p-acetamidophenol g.) in dry dimethylsulfoxide (l l.) and themixture stirred for 30 minutes under a nitrogen atmosphere. To thismixture ,B,B-bis-chloroethyl ether (70 g.) was added and the reactionmixture heated with stirring on a steam bath for 5 days under a nitrogenatmosphere. The reaction mixture was cooled, poured into water (3.5 l.)and throughly extracted with ether. The ether extracts were washed withN-sodium hydroxide, then water, and dried over anhydrous magnesiumsulphate. The ether was evaporated and the resulting oil distilled togive bis-[B-(N-methyl-p-acetamidophenoxy)ethyl] ether b.p. 222C. at 0.05mm of mercury.

Calculated for C H N O C,66.03; H,6.

Found: C,65.86; 11,7

EXAMPLE 39 Aqueous suspensions were prepared having the compositiondetailed below, wherein the compound of formula (l) isB-(4-acetamidophenoxy)ethyl B'-(4-propionamidophenoxy)ethyl ether.

The bentonite was dispersed in some of the water, the BevaloidDispersant and sodium benzoate added, and finally the finely groundactive ingredient and balance of the water. The whole was mixed untiluniform.

Bentonite is a colloidal clay consisting principally of montmorillonite,A1 O HSiO H O, and Bevaloid Dispersant is disodium salt of thecondensation product of naphthalene sulphonic acid and formaldehyde.

EXAMPLE 40 Aqueous suspensions were prepared having the compositiondetailed below, wherein the compound of formula (I) isB-(4-acetamidophenoxy)ethy] B-(4-propionamidophenoxy)ethyl ether.

Compound of formula (I) 30.00% w/w 20.00% w/w 50.00% w/w SuiphitcResidue (Dispersing agent) 5.00% do. 5.00% do. 500% do.(C%lrn:os;4((]fl)|ing agent) 0.75% do. 0.75% do. 0.75% do.

fl! 11!" Water (14.25)? do. 74.25% do. 44.25% do. l00.00/r do. |00.00/1do. 100.00% do.

The Carmoss and sulphite residue were dissolved in the water, the finelyground active ingredient added, Analysis: and h whole mixed until ifCalculated for c n m o c.7102; H,8.94; N,5.l8 Sulphite residue is crudecalcium lignin sulphonate; Found Carmoss is a carragenate or a sulphuricacid ester of a polysaccharide. EXAMPLE 44 EXAMPLE 41 Synthesis ofSynthesis of bis [(4-acetamidophenoxy)methyl]etherblslB44cycloPrOPionamldophenoxy)ethyllatherBis[B-(4-Aminophenoxy)ethyl]ether (7.2g, 0.025 fg z g &3 g2a gg gfg zszigsfigii5 2 3 mole) was dissolved in a mixture of chloroform (I00 mole)added to the warm solution. This solutiod was ml) i pyndme ml) and 9 wastreated then treated with bis(chlor0methyl)ether (9.49g, 0.082 dropwise(.Wer 30 i at 5 l0 C with cyclopropylcap mole) over 10 mins at 20C-After Stirring for 21/2 boxyhc acid chloride (5.7g, 0.055 mole). After2hours hours the mixture was filtered and the solid product Surfing hmixture was mtenid i the produc} Solid washed with dilute aqueous sodiumhydroxide solution g? g dilute g i acld i W3- and with water. Afterdryingthe solid was recrystallized 25 ter rymg. t e so Id f recrysta 3fromo 2- from methylated Spirit mpt' 17250474400 ethoxyethanol withcharcoahng. MPt 189.5 -l9l.l C

i f r C H N O C 62 H 5 85. N 8 14 iil eulmed for c n u o C,67.90; noes;N,6.60 Found 0 2 5 ciszfsoinislsvilvisjoe EXAMPLE 45 EXAMPLE 42Synthesis of l,2-bis(4-acetamidophenoxy)ethane Synthesis of A solutionof sodium ethoxlde, prepared from soblS[B'(4'(Bfil'dlmithlylagrylamldo)phenoxy)e' dium (0.65 g.) and ethanol (15 ml.),was added dropt y let er wise to a stirred solution of p-acetamidophenol(4.25 Bis[B-(4-Aminophenoxy)ethyl]ether (7.0g, 0.024 g.) in ethan0i;(10ml.) at reflux. A mixture of 1,2- mole) was dissolved in a mixture ofchloroform (150 40 dibromoethane (2.65 g.) and ethanol (5 ml.) was ml.)and pyridine (5 ml.) and the solution was treated added dropwise andboiling continued for a further 2 drop-wise with flfir thy y y hl d (50;, hours. After cooling, the solid product was collected by 0.050 m r 1m a 1 Af 2 hours lrfiltration and thoroughly washed with water to yieldring the mixture was filtered and the isolated solid1,2-bis(4-acetamidophenoxy) ethane, m.p. washed with dilute hydrochloricacid and then with wa- 265-266C.; it may be recrystallised from aceticacid ter. After drying the product was recrystallized from2-ethoxyethanol/water with charcoaling to yield crys- EXAMPLE 46 I315,m.pt. 155.9l57.0C. Synthesis of 50Bis[B-(4-acetamidophenoxy)n-propyl]ether Sodium (216g, 0.094 mole) wasdissolved in dried l d f C O C 69 w H 7 3. 6 ethanol (200 ml) andp-hydroxyacetanilide (15.1g, j i or 5 3 hj 51 1 0.100 mole) added. Afterthe p-hydroxyacetanilide had dissolved, bis-B,B'-(mesyloxyn-propyl)ether (11.lg, 55 0.038 mole) was added and the mixture refluxedwith stirring for 37 hours. The ethanol was removed by dis- EXAMPLE 43tillation in vacuo and the residue treated with 2N So- Synthesis of [B-(a p xy) hy l th dium hydroxide and extracted with chloroform. The oilBis[/3 (4 AminophenOXy)ethyuether (72g, 0025 obtained on removing thechloroform was induced to mole) was dissolved in pyridine (75 m1) andtreated solidify by cooling and scratching and the solid was redropwisewith octanoyl chloride (103g, 0.063 mole) at crystaghzed o frommethylated spmt' Mpt -10 to 0C over mins. After stirring for 2 hours,138-3 during which time the temperature was allowed to rise to 20C, themixture was filtered. The isolated solid was washed with dilutehydrochloric acid and then with 65 Anaysis. water and dried beforerecrystallizing from methylated Calculated for cnll u o c.6598; H,7.05,N,7.00 Found C.66.59; H,7.l7 N,7;00

spirit with charcoaling, m.pt. l60.2-16l.5C.

EXAMPLE 47 of chloroacetylchloride (5.0 ml., 0.0625 mole) in chlo- 1roform (25 ml). After stirring for 1 hour the mixture was filtered andthe solid washed with dilute hydrochloric acid and then with waterbefore drying and recrystallizing from 2-ethoxyethanol. MPt170.8-l73.1C.

4.41g. (0.010 mole) of the above-prepared bis[B-(4-chloroacetamidophenoxy)ethyl]ether was treated with dimethylamine (100ml of a 50 percent solution in ethanol) and the mixture kept in apressure vessel for 24 hours at room temperature and then for 16 hoursat 60C. The solvent and excess dimethylamine were then removed bydistillation in vacuo and the residue extracted with dilute hydrochloricacid, charcoaled and filtered before being made alkaline and extractedwith chloroform. Evaporation of the chloroform yielded an oil which wascrystallized from carbon tetrachloride.

MPt 85.687.2C.

Analysis:

Found C,62.60; H,7.44; N,l2.l6

EXAMPLE 48 Synthesis of Bis-[B-(4-N,N-diacetylaminophenoxy)ethyl] EtherA mixture of bis-[B-(4-acetamidophenoxy)ethyl] ether (8.1 g.) and aceticanhydride (40 ml.) was al- 0 lowed to stand at room temperatureovernight. It was then heated at reflux for 6 hours. The reactionmixture was poured into water (1 l). The oil which separated was inducedto crystallize by trituration in the presence of carbon tetrachloride.The resulting solid was recrystallized from an acetone/hexane mixture.The product, which is hygroscopic when moist with the recrystallizationsolvent, was dried at 50C. under reduced pressure, m.p. 9l92C.

ether.

1. BIS-(B(4-N,N-DIACETYLAMINOPHENOXYL) ETHER.